Alzheimer's disease (AD) is associated with specific pathological features, the most prominent being extracellular deposits of amyloid b-peptide (Ab). The accumulation of Ab in the brain results in the formation of plaques, leading to down-stream neuronal death and dementia. A promising avenue for treatment of AD is through the use of selective somatostatin receptor (SSTR) agonists. Somatostatin has been shown to be decreased in humans suffering from AD and specifically regulates neuronal neprilysin activity, a potent Ab-degrading enzyme. Additionally, the somatostatin receptor subtype-4 (SSTR4) is highly expressed in neocortex and hippocampus, areas significantly affected by Ab accumulation in AD patients. We hypothesize that SSTR4 agonists will increase neprilysin activity in the brain leading to decreased Ab concentrations, enhancing learning and memory. The objectives of this grant are to evaluate our novel SSTR4 agonists in their ability to mitigate the decline in memory and learning observed in SAMP8 and transgenic APPswe mice, as well as the corresponding alterations in neprilysin and Ab. This examination has three aims. (1.) Evaluate brain uptake and regional distribution of our novel compounds within the brain. This will allow us to assess the potential viability of respective compounds to adequately enter the brain, establish which regions of the brain they get to, as well as establish appropriate dosing ranges for subsequent aims. (2.) Based on aim-1, selected SSTR4 agonists will be evaluated for learning and memory behavior in mouse models which display learning and memory deficits associated with increased Ab accumulation. This will allow us to identify treatment associated changes in learning and memory retention. (3.) After behavioral evaluations, molecular analyses will be performed on extracted brain tissues to determine the effect of agonist treatment on changes in Ab, SSTR4, amyloid precursor protein (APP) and neprilysin (NEP). These aims will allow us to directly compare the behavioral outcomes with molecular identifiers of AD pathology, with regards to treatment with our SSTR4 agonists. Taken together these analyses will provide new information into the use of SSTR4 agonists for the treatment of AD, as well as shed additional light on the A2 hypothesis. This study addresses priorities of both the NINDS and NIA. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is associated with elevated levels of Amyloid-b peptide (Ab), which acts as a pathological trigger culminating in neuronal death and dementia. A promising avenue for treating AD is in the use of selective and stable somatostatin receptor (SSTR) agonists, which may act to reduce Ab through enhancement of enzymatic degradative processes. This research will evaluate our novel SSTR agonists as to their ability to mitigate Ab concentrations in the brain in conjunction with learning and memory retention, using established models and assessments of AD pathology.